Details

Autor(en) / Beteiligte

• Wang, Hui
• Sun, Tao
• Hu, Jing
• Zhang, Rui
• Rao, Yanhua
• Wang, Shuai
• Chen, Rui
• McLendon, Roger E
• Friedman, Allan H
• Keir, Stephen T
• Bigner, Darell D
• Li, Qi-Jing
• Wang, Huibo
• Wang, Xiao-Fan

Titel

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways

Ist Teil von

• The Journal of clinical investigation, 2014-10, Vol.124 (10), p.4489-4502

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2014

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.